Critical Pathways to Success in CNS Drug Development PDF
Preview Critical Pathways to Success in CNS Drug Development
fm BLBK249-Cutler Trim:6inX9in January19,2010 7:51 CharCount= Critical Pathways to Success in CNS Drug Development Critical Pathways to Success in CNS Drug Development Neal R. Cutler, John J. Sramek, Michael F. Murphy, Henry Riordan, Peter Bieck and Angelico Carta © 2010 NR Cutler, JJ Sramek, MF Murphy, H Riordan, P Bieck and A Carta. ISBN: 978-1-444-33064-9 i fm BLBK249-Cutler Trim:6inX9in January19,2010 7:51 CharCount= Critical Pathways to Success in CNS Drug Development Neal R. Cutler, M.D. PresidentandCEO,WorldwideClinicalTrials BeverlyHills,CA,USA John J. Sramek, Pharm. D. DirectorofClinicalResearch,WorldwideClinicalTrials BeverlyHills,CA,USA Michael F. Murphy, M.D., Ph.D. ChiefMedicalandScientificOfficer,WorldwideClinicalTrials KingofPrussia,PA,USA Henry Riordan, Ph.D. Sr.VPMedicalandScientificAffairs,WorldwideClinicalTrials KingofPrussia,PA,USA Peter Bieck, M.D., Ph.D. VicePresidentofClinicalResearch,WorldwideClinicalTrials Indianapolis,IN,USA Angelico Carta, M.D. President,WorldwideClinicalTrialsEurope London,UK A John Wiley & Sons, Ltd., Publication iii fm BLBK249-Cutler Trim:6inX9in January19,2010 7:51 CharCount= Thiseditionfirstpublished2010,(cid:1)c 2010byNRCutler,JJSramek,MFMurphy,HRiordan,PBieck andACarta BlackwellPublishingwasacquiredbyJohnWiley&SonsinFebruary2007.Blackwell’spublishing programhasbeenmergedwithWiley’sglobalScientific,TechnicalandMedicalbusinesstoform Wiley-Blackwell. Registeredoffice: JohnWiley&SonsLtd,TheAtrium,SouthernGate,Chichester,WestSussex,PO198SQ,UK Editorialoffices:9600GarsingtonRoad,Oxford,OX42DQ,UK TheAtrium,SouthernGate,Chichester,WestSussex,PO198SQ,UK 111RiverStreet,Hoboken,NJ07030-5774,USA Fordetailsofourglobaleditorialoffices,forcustomerservicesandforinformationabouthowto applyforpermissiontoreusethecopyrightmaterialinthisbookpleaseseeourwebsiteat www.wiley.com/wiley-blackwell Therightoftheauthortobeidentifiedastheauthorofthisworkhasbeenassertedinaccordancewith theCopyright,DesignsandPatentsAct1988. Allrightsreserved.Nopartofthispublicationmaybereproduced,storedinaretrievalsystem,or transmitted,inanyformorbyanymeans,electronic,mechanical,photocopying,recordingor otherwise,exceptaspermittedbytheUKCopyright,DesignsandPatentsAct1988,withouttheprior permissionofthepublisher. Wileyalsopublishesitsbooksinavarietyofelectronicformats.Somecontentthatappearsinprint maynotbeavailableinelectronicbooks. Designationsusedbycompaniestodistinguishtheirproductsareoftenclaimedastrademarks.All brandnamesandproductnamesusedinthisbookaretradenames,servicemarks,trademarksor registeredtrademarksoftheirrespectiveowners.Thepublisherisnotassociatedwithanyproductor vendormentionedinthisbook.Thispublicationisdesignedtoprovideaccurateandauthoritative informationinregardtothesubjectmattercovered.Itissoldontheunderstandingthatthepublisher isnotengagedinrenderingprofessionalservices.Ifprofessionaladviceorotherexpertassistanceis required,theservicesofacompetentprofessionalshouldbesought. Thecontentsofthisworkareintendedtofurthergeneralscientificresearch,understanding,and discussiononlyandarenotintendedandshouldnotberelieduponasrecommendingorpromotinga specificmethod,diagnosis,ortreatmentbyphysiciansforanyparticularpatient.Thepublisherand theauthormakenorepresentationsorwarrantieswithrespecttotheaccuracyorcompletenessofthe contentsofthisworkandspecificallydisclaimallwarranties,includingwithoutlimitationany impliedwarrantiesoffitnessforaparticularpurpose.Inviewofongoingresearch,equipment modifications,changesingovernmentalregulations,andtheconstantflowofinformationrelatingto theuseofmedicines,equipment,anddevices,thereaderisurgedtoreviewandevaluatethe informationprovidedinthepackageinsertorinstructionsforeachmedicine,equipment,ordevicefor, amongotherthings,anychangesintheinstructionsorindicationofusageandforaddedwarnings andprecautions.Readersshouldconsultwithaspecialistwhereappropriate.Thefactthatan organizationorWebsiteisreferredtointhisworkasacitationand/orapotentialsourceoffurther informationdoesnotmeanthattheauthororthepublisherendorsestheinformationtheorganization orWebsitemayprovideorrecommendationsitmaymake.Further,readersshouldbeawarethat InternetWebsiteslistedinthisworkmayhavechangedordisappearedbetweenwhenthisworkwas writtenandwhenitisread.Nowarrantymaybecreatedorextendedbyanypromotionalstatements forthiswork.Neitherthepublishernortheauthorshallbeliableforanydamagesarisingherefrom. LibraryofCongressCataloging-in-PublicationData CriticalpathwaystosuccessinCNSdrugdevelopment/NealR.Cutler...[etal.]. p.;cm. Includesbibliographicalreferencesandindex. ISBN978-1-4443-3064-9 1.Neuropsychopharmacology. 2.Drugdevelopment. 3.Criticalpathanalysis. 4.Central nervoussystem–Effectofdrugson–Research–Methodology. I.Cutler,NealR. [DNLM:1.CentralNervousSystemAgents–pharmacology. 2.ClinicalTrialsasTopic–methods. 3.DrugEvaluation–methods. 4.DrugEvaluation,Preclinical–methods.QV76.5C9342010] RM315.C7152010 615(cid:1).78–dc22 2009035146 AcataloguerecordforthisbookisavailablefromtheBritishLibrary. Setin9.5/12ptPalatinobyAptara(cid:2)R Inc.,NewDelhi,India PrintedinSingapore 1 2010 iv fm BLBK249-Cutler Trim:6inX9in January19,2010 7:51 CharCount= Contents Acknowledgments,vi Foreword,vii 1 TheimpendingcrisisinCNSdrugdevelopment,1 2 AnimalmodelsandproceduresforCNSdisorders,14 3 Preclinicalantecedentstoearlyhumanclinicaltrials,70 4 Biomarkersandsurrogatemarkersindrugdevelopment,101 5 Neuroimagingandcognitiveassessmentsinearlydrug development,167 6 BridgingandCSFstudies,187 7 Acasestudyfrompreclinicaltoearlyclinicaltrials,230 Index,254 v fm BLBK249-Cutler Trim:6inX9in January19,2010 7:51 CharCount= Acknowledgments TheauthorsaregratefultoAndrewKuhlmanforhisinvaluableassistancein helpingthemresearchtheliterature,formattables,andwritethepresentbook. Hewasevervigilantinorganizinglargesectionsofthetext,keepingtrackof countless references, and integrating comments from all the authors with a unifiedwritingstyle. We also wish to thank Tricia Long for her assistance with Chapter 6, and William Nowatzke, Ph.D., for his contribution on laboratory biomarkers in Chapter4. vi fm BLBK249-Cutler Trim:6inX9in January19,2010 7:51 CharCount= Foreword The process of drug development has never been as complex and costly as ithasbecomeinthetwenty-firstcentury.Encouragedbysensationalisticand inaccuratereportinginthelaypress,manycitizensareconvincedoftheunre- alisticfantasythatprescriptionpharmaceuticalproductsshouldberisk-free. Wheneffectivemedicationscauseadversereactions—astheyinevitablydo— theresponsefromthepublicandfrompoliticiansisoutrage,withaccusations of greed and malfeasance on the part of the pharmaceutical manufacturers andincompetenceonthepartofregulatoryagencies.Theoutcomehasbeen a development process driven by avoidance of liability and blame, with an increasingmazeofpaperworkandregulationthatworkagainsttrueinnova- tion. Fordevelopersofnewdrugsintheareaofneuropsychopharmacology,the alreadydifficultprocessisfurthercomplicatedbyfeaturesintrinsictothedis- cipline. Mood, affect, thought, behavior, and cognition are not easily mea- sured.Outcomeinstrumentsare“soft,”andresponsespotentiallymodulated byresearchsetting,experience,expectations,andpractice.Experimentalani- malmodelsandsurrogatemarkersofdiseaseandtreatmentarelesswellde- velopedthaninotherdisciplines.Placeboresponseratesintrialsofneuropsy- chiatric agents are uncomfortably high, leading to many “failed” studies in whichevenanestablishedactivecomparatordoesnotseparatefromplacebo. I have known Dr. Neal Cutler and his work for more than three decades. His career represents a remarkable blend of academic achievement and en- trepreneurialsuccess.Aphysicianandboard-certifiedpsychiatrist,Dr.Cutler spenthisearlyprofessionalcareerasanacademicpsychiatrist,bothattheUni- versityofCaliforniaandattheNationalInstitutesofHealth.In1987hestarted asuccessfulclinicaltrialsite,andsubsequentlyacontractresearchorganiza- tion(CRO)inBeverlyHills,specializinginclinicaltrialsofmarketedandcan- didatedrugsinpsychiatryandneurology.HisworkintheCROindustryhas broughthimtohispresentpositionasPresidentandChiefExecutiveOfficer ofWorldwideClinicalTrialsinBeverlyHills. TheaccomplishmentsofDr.Cutlerandhisassociatesdemonstratethatafi- nanciallysuccessfulCROcannotonlyservethedrugdevelopmentobjectives ofthepharmaceuticalindustry,butalsoadvancebasicandclinicalknowledge inneuropsychopharmacology.Overtheyearstheirworkhasresultedinhun- dreds of publications in the peer-reviewed medical and scientific literature. Thevastexperienceofthegrouprangesfromstrategicscientificandconcep- tualaspectsofdrugdevelopmentinpsychopharmacologytopracticalissues vii fm BLBK249-Cutler Trim:6inX9in January19,2010 7:51 CharCount= viii Foreword ofprotocoldesignandexecution,avoidanceoftypicalproblemsandpitfalls, andcompliancewithregulatoryrequirements. This book collates and summarizes the experiences of Dr. Cutler and his professionalcolleagues.Itisnotananthologyofchaptersfromdifferentau- thors at different institutions—each chapter is written by Dr. Cutler and his collaboratingscientistsatWorldwideClinicalTrials,Inc.Itistheirexperience, expertise,andachievementthatarerepresentedontheprintedpage.Forthose determinedenoughtofacethehazardouslandscapeofdrugdevelopmentin neuropsychopharmacology,thisbookwillhelp. DavidJ.Greenblatt,MD Boston,MA c01 BLBK249-Cutler Trim:6inX9in December29,2009 20:14 CharCount= CHAPTER 1 The impending crisis in CNS drug development Introduction Aplethoraofinformationhasbeengatheredacrossthefieldsofneuroimag- ing, genetics/genomics, proteomics, neurobiology, and epidemiology that have greatly enhanced our basic knowledge of the pathophysiological and genetic underpinnings of many common central nervous system (CNS) dis- orderssuchasschizophrenia,Alzheimer’sdisease(AD),Parkinson’sdisease, depression, and anxiety disorders. In fact, most of what is currently known abouttheseCNSdisordershasbeendiscoveredinthepastdecade.However, thesebreakthroughsintheCNSbasicscienceshavetoooftenfailedtotrans- late into more effective, more affordable, and safer pharmaceutical products forpatientssufferingfromthesedisorders.Muchoftheinformationresulting fromtheseinnovationshashadlittleclinicalrelevance,anddespitethenewly acquiredknowledgegainedthroughoutthepastfewyears,CNSdrugdevel- opmenthasbeencharacterizedbyrelativestagnation.Infact,thenumberof approvalsforCNSdrugsoverthepastseveralyearshasactuallydeclined! Given the current economic climate in the US and around the world, this situation appears to be only getting worse—there are reduced resources available for drug development and reduced capital to fund this develop- ment. In addition, the drug development pathway is typically cumbersome and expensive, requiring fresh ideas and streamlined procedures to make developmentprogramsrunfasterandcheaper,aswellasupdatedregulations fromtheFoodandDrugAdministration(FDA)tosimplifythedrugapproval process.Manyoftheseinnovationsalreadyexist,andarebeginningtobein- tegratedintothedrugdevelopmentpipeline.Othersarebeingvalidatedand maysoonbecomevitalcomponentsofthispathway.Thepharmaceuticaland biotechnologyindustriesareonthecuspofamajorrevolutionintechnology, procedures,andregulationsregardingdrugdevelopment—notbecausethey wish to improve upon an already successful system, but because they need toreplaceaflawedandbrokensystemiftheywishtoberelevantincoming decades,andcreatenew,effectivetreatmentsforthepatientswhoneedthem themost. Critical Pathways to Success in CNS Drug Development Neal R. Cutler, John J. Sramek, Michael F. Murphy, Henry Riordan, Peter Bieck and Angelico Carta © 2010 NR Cutler, JJ Sramek, MF Murphy, H Riordan, P Bieck and A Carta. ISBN: 978-1-444-33064-9 1 c01 BLBK249-Cutler Trim:6inX9in December29,2009 20:14 CharCount= 2 Chapter1 It is with this idea in mind that we have decided to write this book. We have compiled the latest advances in early CNS drug development from a vast body of literature, from clinical studies, and from our own experience. Wehaveexplainedtheseadvancesinsequential,clearlyorganizedchapters, beginningwithpreclinicalmodelsandgoingthroughfirst-in-manclinicaltri- als.Wehaveprovidedconcise,relevantsummariesandreviewsofthenewest techniques, markers, and models being used and introduced into the CNS drug development pipeline, and determined how they can be best utilized andwhatfurthervalidationisrequired.WehavealsoreviewedthelatestFDA regulationsandguidelines,anddiscussedhoweachoftheseaffectsthedrug developmentindustryforbetterorforworse. However, before we discuss the many innovations and regulations de- signedtoaddresstheproblemsthedrugdevelopmentindustryfaces,wewish to briefly explain the problems themselves; this way you will have a better understandingofwhatrequiresfixing,whyitneedstobefixed,andjusthow serioustheproblemsreallyare. Stagnation in CNS drug development The current stagnation in CNS drug development is evidenced by the lack ofnoveltreatmentsacrossanumberofneurologicandpsychiatricdisorders, withtwoofthemostrepresentativeindicationsfromthetherapeuticareaof CNS(ADandschizophrenia)servingascompellingillustrationsofthisstag- nation.Forexample,thelackofapprovabletherapiesthatwouldhopetomod- ifydiseaseprogressionofADhasbeentrulyfrustrating—notonlyforphysi- ciansandfamilymemberswhoarecaregiversforpatientswithAD,butalso forsocietyasawhole,giventheloomingfinancialandhealthcarecrisisassoci- atedwiththeever-increasingprevalenceofthedisease.Todate,allthedrugs approvedtotreatAD,includingtheN-methyl-d-asparticacid(NMDA)antag- (cid:1) onistNamendaR (memantine),aswellasallofthecholinesteraseinhibitors, (cid:1) (cid:1) including RazadyneR (galantamine/previously known as ReminylR), (cid:1) (cid:1) ExelonR (rivastigmine), and AriceptR (donepezil), are prescribed for the treatmentofthesymptomsofADandcarrythelabelthatthereis“noevidence thatanyofthesedrugsalterthecourseoftheunderlyingdementingprocess.” As an example, despite an explosion of publications advancing our un- derstanding of the diagnostics, pathophysiology, genetics, and imaging associated with AD, there have not been any drugs that have successfully been shown to act as “disease modifiers.” This is certainly not for a lack of effort: In early 2007, there were approximately 12 drugs in US phase III clinical trials for AD, all of which showed great promise to slow or stop the progressionofthediseasebasedontheirmechanismsofaction.Additionally, the European Medicines Agency (EMEA) reported consulting on at least 15 different AD drugs, with 79% of their advice stemming from queries surroundingdiseasemodification(20%wereonsymptomatictreatmentand c01 BLBK249-Cutler Trim:6inX9in December29,2009 20:14 CharCount= TheimpendingcrisisinCNSdrugdevelopment 3 1%wereondiagnostics)[1].Despitesomeearlysignalstothecontrary,there (cid:1) arenodevelopmentprogramstodate(includingNeurochem’sAlzhemedR, Myriad Genetics’ FlurizanTM, and Wyeth/Elan’s bapineuzumab) that have unequivocallyshownpositivetrialresults,althoughsomeinterestingtrends werenotedthatwillbediscussedbelow. The lack of disease modifiers is especially dire when considering that the Alzheimer’sAssociationreportfromMarchof2007concludedthattherewere over 5 million people in the United States living with AD [2]. This number includes4.9millionpeopleovertheageof65andbetween200,000and500,000 peopleundertheageof65withearly-onsetADandotherdementias.Equally alarmingaretheprojectionsforthefuture.TheprevalenceofADispredicted to increase 27% by 2020, an astonishing 70% by 2030, and nearly 300%, to approximately 13.2 million people, by 2050—unless a way can be found to slowtheprogressionofthediseaseorpreventit[3].Remarkably,ithasbeen suggested that even a “5-year delay in onset could reduce the prevalence of ADbyalmost50%”[4],underscoringtheneedforadrugthatwilldelaythe onset or progression of dementia. The prevalence projections for AD are in starkcontrasttootherindicationssuchasheartdiseaseandcancer,whichare projected to remain stable or actually decline over time. From 2000 to 2005, death rates have declined for most major diseases—including heart disease, breastcancer,andprostatecancer—whiledeathsfromADcontinuetotrend upward,andareexpectedtoincrease44%by2025[5]. Another regrettable example of stagnation in the field of CNS therapies comes from psychiatry, and is evidenced by the lack of novel antipsychotic drugs to treat schizophrenia and other psychotic disorders. The three-phase ClinicalAntipsychoticTrialsofInterventionEffectiveness(CATIE)study,one ofthelongestdrugtrialseverconductedinpsychiatry,beganin2000anddata wereanalyzedbeginningin2005.Inthattimeperiod,onlytwonewantipsy- (cid:1) (cid:1) choticdrugs(ziprasidone[marketedasGeodonR andZeldoxR]in2001and (cid:1) AbilifyR in 2002) were approved. Since then, only one other drug has been approved for the treatment of schizophrenia—Janssen’s InvegaTM (paliperi- done),whichwasapprovedin2006.Invegaisanoralextended-release(ER) major active metabolite of risperidone and would not be considered to be a novelmolecularentityornewmolecularentity(NME). InthefirstphaseoftheCATIEstudy,1493patientswithschizophreniawere recruited at 57 US sites and were randomly assigned to receive the antipsy- chotics olanzapine (7.5–30 mg/day), perphenazine (8–32 mg/day), quetiap- ine(200–800mg/day),orrisperidone(1.5–6.0mg/day)forupto18months. Ziprasidone (40–160 mg/day) was added in 2002 following its approval by the FDA. The study concluded that the majority of patients in each treat- ment group discontinued due to inefficacy or intolerable side effects or for otherreasons.Patientsonolanzapinehadthebestrecordforcontinuingtreat- ment, but this treatment was associated with greater weight gain and in- creasesinmeasuresofglucoseandlipidmetabolism.Overall,74%ofpatients
The list of books you might like
